Comparative analysis of the omics technologies used to study antimonial, amphotericin B, and pentamidine resistance in leishmania

Abstract

Leishmaniasis is a serious threat in developing countries due to its endemic nature and debilitating symptoms. Extensive research and investigations have been carried out to learn about the mechanism of drug resistance in Leishmania but results obtained in the laboratory are not in agreement with those obtained from the field. Also the lack of knowledge about the mode of action for a number of drugs makes the study of drug resistance more complex. A major concern in recent times has been regarding the role of parasitic virulence in drug resistance for Leishmania. Researchers have employed various techniques to unravel the facts about resistance and virulence in Leishmania. With advent of advanced and more specific means of detection, further hints about probable mechanisms of conferring resistance are expected. This review aims to provide a consolidated picture along with a comparative account of the work done so far to study the mechanism of antimony, amphotericin B, and pentamidine resistance using various techniques.

Figure 1

The mechanisms of antimony resistance in Leishmania. (a) Activation: conversion of Sb (V) to Sb (III) is inhibited in R-cells. This inhibition can either occur extracellularly (by inactivation of enzymes still unknown) or intracellularly (by inhibition of enzymes like ACR2 or TDR1). (b) Decreased uptake: decreased expression of AQP1 reduces Sb uptake into the cell thus conferring resistance. (c) Conjugation and sequestration: increased thiol levels (like cysteine (Cys), GSH, TSH, and polyamines) in the cell result in its conjugation with antimony to form antimony-thiol complex (Sb-TS) which then results in sequestration of the complex into a cell organelle or extrusion from the cell thus lowering intracellular amount of antimony. Blue lines indicate the probable drug action in sensitive Leishmania strains while red lines depict the probable routes to achieve resistance as observed in resistant cells.

Figure 2

The mechanisms of amphotericin B resistance in Leishmania. (a) Change in membrane fluidity results in blocking of the drug entry inside the cell. The membrane transporters or factors responsible for such changes in membrane depolarization are still unknown. (b) Gene amplification of genes to confer resistance. (c) Activation of tryparedoxin cascade to prevent the oxidative damage caused by the drug. (d) Drug efflux through various membrane-bound pumps like MDR1.

Figure 3

The mechanisms of pentamidine resistance in Leishmania. (a) Change in kDNA sequence confers resistance. The exact mechanism of conferring resistance remains unknown. (b) Presence of drug efflux pumps like PRP1 to remove the drug molecules from the cell and thus protect it from damage. (c) Reduced uptake of pentamidine in mitochondria due to altered polyamine biosynthetic pathways and lowered membrane potential. Blue lines indicate the probable drug action in sensitive Leishmania strains while red lines depict the probable routes to achieve resistance as observed in resistant cells.